Although it has been know for some time that multiple sclerosis (MS) is more frequently observed in women than in men (2-3:1), it is not known why. Current theories suggest that men may suffer a different type of MS and/or show more severity in their symptoms as compared to the milder relapsing-remitting disease frequently seen in females. It is thought that immune responses, such as responses to infectious agents and autoimmune reactivity, are sexually dimorphic. While these differences are likely influenced by sex steroids, current theories fail to account for the fact that hormone levels themselves are unlikely to vary widely between affected and non-affected men, or affected and non- affected women. Instead, what is likely to be different is an individual's unique genetic profile of sexually responsive genes. Many immunologically significant genes are quite sensitive to the presence (or absence) of sex-steroids and sex-related soluble factors. Additionally, other genes that control the conversion of sex-steroids into immunologically more active forms could have significant influence on the clinical course of MS. This proposal uses genetic crosses of mice that differ in susceptibility to experimental autoimmune encephalomyelitis (EAE), the best-studied animal model of MS, to identify genes important in their ability to regulate the sexually dimorphic susceptibility see in MS and EAE.